Balloon catheter devices with solvent-swellable polymer

ABSTRACT

Methods for making a balloon catheter device comprising a solvent-swellable polymer are provided. The method includes providing a balloon, wherein a wall of the balloon or a coating over the balloon comprises a polymer, wherein the polymer is swellable in an organic solvent. In certain embodiments of the invention, the polymer on the balloon is exposed to a mixture of said solvent and a therapeutic agent; and the solvent is thereafter removing, leaving the therapeutic agent in the polymer.

RELATED APPLICATIONS

This application claims the benefit of provisional application Ser. No.61/034,328, filed Mar. 6, 2008, which is incorporated herein byreference in its entirety.

TECHNICAL FIELD

The present invention relates to medical devices, more particularly, tocatheter devices.

BACKGROUND

Catheters are used in a wide variety of minimally-invasive orpercutaneous medical procedures. Balloon catheters having drug coatingsmay be used to treat diseased portions of blood vessels. Typically, theballoon is inserted through a peripheral blood vessel and then guidedvia a catheter through the vascular system to the target intravascularsite. However, as the balloon travels through the vascular system, theflow of blood may wash away some of the drug coating. In addition, thecontrol of the timing, location and/or duration of the release of thedrug can be an issue. Therefore, there is a need for improvedcatheter-based devices for drug delivery to an intravascular site.

SUMMARY

In one embodiment, the present invention provides a method for making amedical device, comprising: providing a balloon, wherein a wall of theballoon or a coating over the balloon comprises a polymer, wherein thepolymer is swellable in an organic solvent; exposing said polymer to amixture of said solvent and a therapeutic agent; and removing thesolvent.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A and 1B show a catheter device according to an embodiment of thepresent invention. FIG. 1A shows the catheter device with the balloon ina deflated state. FIG. 1B shows the catheter device with the balloon inan inflated state.

FIGS. 2A-2C schematically illustrate a polymer matrix in a balloon wallor a balloon coating according to an embodiment of the presentinvention. FIG. 2A shows the polymer matrix prior to solvent exposure.FIG. 2B shows the polymer matrix in an expanded condition after exposureto a mixture of a solvent and a therapeutic agent. FIG. 2C shows thepolymer matrix in a contracted condition after the removal of thesolvent.

DETAILED DESCRIPTION

Catheter devices of the present invention use an expandable balloon fordelivering a therapeutic agent to a target site in the body. The balloonis designed to be insertable in the body via a catheter. The therapeuticagent can be associated with the balloon in any of various ways, asfurther described below. Any of various mechanisms conventionally usedfor the delivery, actuation, or expansion (e.g., by inflation) ofballoon catheter devices may be used in the present invention. Theballoon catheter may be designed similar to those that have been knownin the art, including but not limited to angioplasty catheters, stentdelivery catheters, inflation catheters and/or perfusion catheters. Thecatheter devices of the present invention may be used in conjunctionwith other drug delivery devices, such as stents.

Referring to FIGS. 1A and 1B, in certain embodiments, a balloon catheter20 comprises a catheter body 22 having a balloon 24 mounted thereon. InFIG. 1A, the balloon is in a deflated state; in FIG. 1B, the balloon isin an inflated state. The body of the balloon can be single-layered ormultiple-layered.

In one aspect of the present invention, a balloon comprises asolvent-swellable polymer. The solvent-swellable polymer may have atherapeutic agent incorporated therein and may be used to form a wall ofthe balloon or to form a coating disposed over the balloon.

Preferably, the polymer is swellable upon exposure to an organicsolvent. The organic solvent can be polar or non-polar. Preferably, theorganic solvent has a low boiling point. Preferably, the organic solventhas a boiling point of about 90° C. or less, about 80° C. or less, orabout 70° C. or less. Solvents with low boiling points can be removedrelatively easier than those with high boiling points. Non-limitingexamples of organic solvents include dichloromethane, chloroform, carbontetrachloride, ethyl acetate, tetrahydrofuran, acetonitrile, hexane, andcyclohexane.

Optionally, the solvent-swellable polymer is a semi-crystalline polymer.The semi-crystalline polymer can form a polymer matrix havingcrystalline portions and amorphous portions. When the polymer matrix isexposed to a mixture of a suitable organic solvent and a therapeuticagent, the solvent and the therapeutic agent diffuses into and swellspreferentially the amorphous regions of the polymer matrix. Thecrystalline portions of the polymer matrix are more resistant toswelling, and therefore form a stable structure that maintains thephysical structure of the polymer-containing balloon wall or coating.When the solvent is removed, the polymer matrix contracts to itsoriginal conformation, entrapping the therapeutic agent within thepolymer matrix.

For example, referring to the schematic illustration shown in FIGS.2A-2C, a catheter device comprises a balloon comprising asolvent-swellable, semi-crystalline polymer. FIG. 2A shows a polymermatrix 70 on the wall of the balloon prior to solvent exposure. Polymermatrix 70 has crystalline regions 72, which are representedschematically by the lines, and amorphous regions 74, which arerepresented schematically by the spaces. Referring to FIG. 2B, uponexposure to a mixture of a solvent and a therapeutic agent, amorphousregions 74 absorb the solvent and therapeutic agent 76, causing polymermatrix 70 to swell. Referring to FIG. 2C, upon removal of the solvent,polymer matrix 70 contracts to its original conformation such thattherapeutic agent 76 is retained within polymer matrix 70.

Optionally, the solvent-swellable polymer is a partially cross-linkedpolymer. Preferably, the cross-linking density is low to allow at leasta portion of the polymer to swell in an organic solvent. Thecross-linking can be done using any known methods. For example, thecross-linking may be induced by UV irradiation or electron beamirradiation. The cross-linked portions of the polymer serve as thestable structure, while the non-crosslinked portions of the polymerswell upon exposure to an organic solvent and entrap the therapeuticagent previously mixed with the solvent after the solvent is removed.

Optionally, the solvent-swellable polymer is grafted onto the surface ofthe balloon through chemical bonding. In this case, the balloon wallbase itself serves as the stable structure, while the polymer swellsupon exposure to an organic solvent and entraps the therapeutic agentpreviously mixed with the solvent after the solvent is removed.

Non-limiting examples of solvent-swellable polymers include blockcopolymers of styrene-ethylene/butylene-styrene (“SEBS”), blockcopolymers of styrene-ethylene/propylene-styrene (“SEPS”), blockcopolymers of styrene-butadiene-styrene (“SBS”), block copolymers ofstyrene-isoprene-styrene (“SIS”), polyolefins such as polyethylene andpolypropylene, polyurethane, polyoxymethylene-acetyl copolymers,polyamide block copolymers, and copolymers of acrylates andmethacrylates. The SEBS, SEPS, SBS, and SIS copolymers can becommercially-available copolymers, such as those sold under the tradenames KRATON G and KRATON D. Preferably, the solvent-swellable polymerhas unsaturated bonds to allow for cross-linking or grafting.

After the therapeutic agent is loaded into the polymer, the solvent maybe removed by any known method, for example, evaporation or vacuumdrying. Preferably, the solvent is removed without heating. Preferably,the solvent is removed by evaporation.

In operation, the balloon comprising a therapeutic agent-containingpolymer is inserted into the body and delivered to the target site. Theballoon is then inflated, causing the polymer (in the case of asemi-crystalline polymer being used, polymer matrix 70) in the balloonwall to undergo expansion by mechanical force. By enlarging the spacewithin the polymer (e.g. polymer matrix 70), the therapeutic agent (e.g.therapeutic agent 76) is released from the wall of the balloon. Becausethe therapeutic agent is preferably loaded through diffusion, it tendsto locate near the surface of the wall or coating and can be easilyreleased after the balloon catheter device is delivered to the targetsite.

Medical devices of the present invention may also include a vascularstent mounted on the balloon. The vascular stent may be any of thoseknown in the art, including those with or without coatings that containa therapeutic agent. The stent may also be biostable, bioerodable, orbiodegradable.

The balloons of the present invention may also be coated with alow-molecular weight carbohydrate, such as mannitol. The carbohydratemay be a separate coating or be blended with the therapeutic agent. Theballoons of the present invention may also be coated with aradiocontrast agent (ionic or non-ionic), such as iopromide. Thecontrast agent may be a separate coating or be blended with thetherapeutic agent.

The therapeutic agent used in the present invention may be anypharmaceutically acceptable agent (such as a drug), a biomolecule, asmall molecule, or cells. Example drugs include anti-proliferativeagents or anti-restenosis agents such as paclitaxel, sirolimus(rapamycin), tacrolimus, everolimus, and zotarolimus. Other exampledrugs include those that are anti-spasmodic agents and vasodilators.Example biomolecules include peptides, polypeptides and proteins;antibodies; oligonucleotides; nucleic acids such as double or singlestranded DNA (including naked and cDNA), RNA, antisense nucleic acidssuch as antisense DNA and RNA, small interfering RNA (siRNA), andribozymes; genes; carbohydrates; angiogenic factors including growthfactors; cell cycle inhibitors; and anti-restenosis agents. Examplesmall molecules include hormones, nucleotides, amino acids, sugars, andlipids and compounds have a molecular weight of less than 100 kD.Example cells include stem cells, progenitor cells, endothelial cells,adult cardiomyocytes, and smooth muscle cells.

EXAMPLE 1

A double-layered balloon is manufactured. The inner layer is made ofhigh density polyethylene and the outer layer is made of SEBS (KRATON G,Kraton Polymers, Houston, Tex.). The SEBS in the outer layer iscrosslinked by electron beam irradiation. The balloon is then immersedin a mixture of cyclohexane and paclitaxel for drug loading. After theballoon is taken out, the cyclohexane is removed by evaporation. Theballoon is then assembled onto a balloon catheter device.

The foregoing description and examples have been set forth merely toillustrate the invention and are not intended to be limiting. Each ofthe disclosed aspects and embodiments of the present invention may beconsidered individually or in combination with other aspects,embodiments, and variations of the invention. Modifications of thedisclosed embodiments incorporating the spirit and substance of theinvention may occur to persons skilled in the art and such modificationsare within the scope of the present invention.

1. A method for making a medical device, comprising: providing aballoon, wherein a wall of the balloon or a coating over the ballooncomprises a polymer, wherein the polymer is swellable in an organicsolvent; exposing said polymer on the balloon to a mixture of saidsolvent and a therapeutic agent; and removing the solvent.
 2. The methodof claim 1, wherein a wall of the balloon comprises the polymerswellable in an organic solvent.
 3. The method of claim 1, wherein acoating over the balloon comprises the polymer swellable in an organicsolvent.
 4. The method of claim 3, wherein the polymer is grafted to awall of the balloon through chemical bonding.
 5. The method of claim 1,wherein the polymer is a semi-crystalline polymer comprising crystallineregions and amorphous regions.
 6. The method of claim 1, wherein thepolymer is partially cross-linked.
 7. The method of claim 1, wherein thepolymer is selected from the group consisting of block copolymers ofstyrene-ethylene/butylene-styrene, block copolymers ofstyrene-ethylene/propylene-styrene, block copolymers ofstyrene-butadiene, block copolymers of styrene-isoprene, polyolefins,polyurethane, polyoxymethylene-acetyl copolymers, polyamide blockcopolymers, copolymers of acrylates and methacrylates, and mixturesthereof.
 8. The method of claim 7, wherein the polymer is selected fromthe group consisting of block copolymers ofstyrene-ethylene/butylene-styrene, block copolymers ofstyrene-ethylene/propylene-styrene, block copolymers ofstyrene-butadiene, block copolymers of styrene-isoprene, polyurethane,and mixtures thereof.
 9. The method of claim 1, wherein the solvent is apolar organic solvent.
 10. The method of claim 1, wherein the solvent isa non-polar organic solvent.
 11. The method of claim 1, wherein theboiling point of the solvent is about 90° C. or less.
 12. The method ofclaim 1, wherein the solvent is selected from the group consisting ofdichloromethane, chloroform, carbon tetrachloride, ethyl acetate,tetrahydrofuran, acetonitrile, hexane, cyclohexane, and mixturesthereof.
 13. The method of claim 1, wherein the solvent is removed byevaporation.
 14. The method of claim 1, wherein the therapeutic agent isselected from the group consisting of paclitaxel, sirolimus, tacrolimus,everolimus, zotarolimus, and mixtures thereof.
 15. A method of releasinga therapeutic agent from the surface of a balloon catheter comprising:providing a balloon, wherein a wall of the balloon or a coating over theballoon comprises a polymer, wherein the polymer is swellable in anorganic solvent; exposing said polymer on the balloon to a mixture ofsaid solvent and a therapeutic agent; removing the solvent; andexpanding the balloon to release the therapeutic agent.
 16. The methodof claim 15, wherein the polymer is grafted to a wall of the balloonthrough chemical bonding.
 17. The method of claim 15, wherein thepolymer is a semi-crystalline polymer comprising crystalline regions andamorphous regions.
 18. The method of claim 15, wherein the polymer ispartially cross-linked.
 19. The method of claim 15, wherein the boilingpoint of the solvent is about 90° C. or less.
 20. The method of claim15, wherein the solvent is removed by evaporation.